PMID- 30962677
OWN - NLM
STAT- MEDLINE
DCOM- 20190916
LR  - 20220410
IS  - 1177-8881 (Electronic)
IS  - 1177-8881 (Linking)
VI  - 13
DP  - 2019
TI  - Single- and multiple-dose tolerability, safety, pharmacokinetics, and 
      pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in 
      healthy adult and elderly subjects.
PG  - 949-964
LID - 10.2147/DDDT.S199051 [doi]
AB  - BACKGROUND: Aprocitentan is an orally active, dual endothelin (ET) receptor 
      antagonist developed for the treatment of hypertension in which, despite 
      available treatments, a medical need exists for drugs with a new mechanism of 
      action. SUBJECTS AND METHODS: In this study, the single- and multiple-dose 
      tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg 
      (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were 
      investigated in healthy male and female subjects. The effect of age on the 
      tolerability and PK parameters was investigated at a dose of 100 mg qd. RESULTS: 
      Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) 
      occurred. The most frequently reported AE was headache. Small increases in body 
      weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time 
      profiles of aprocitentan were similar after single- and multiple-dose 
      administration, and support a qd dosing regimen based on a half-life of 44 hours. 
      After multiple doses, PK was dose proportional. Accumulation at steady state, 
      reached by Day 8, was 3-fold. Only minor differences in exposure between healthy 
      females and males, healthy elderly and adult subjects, and fed and fasted 
      conditions were observed. Plasma ET-1 concentrations, reflecting ET(B) receptor 
      antagonism, significantly increased with doses >/=25 mg. Time-matched analysis of 
      electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. 
      Exposure-response analysis indicated no QTc prolongations at plasma levels up to 
      10 microg/mL. CONCLUSION: Aprocitentan was well tolerated in healthy subjects with a 
      PK profile favorable for qd dosing.
FAU - Sidharta, Patricia N
AU  - Sidharta PN
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil 
      CH-4123, Switzerland, patricia.sidharta@idorsia.com.
FAU - Melchior, Meggane
AU  - Melchior M
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil 
      CH-4123, Switzerland, patricia.sidharta@idorsia.com.
FAU - Kankam, Martin K
AU  - Kankam MK
AD  - Vince and Associates Clinical Research, Overland Park, KS 66211, USA.
FAU - Dingemanse, Jasper
AU  - Dingemanse J
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil 
      CH-4123, Switzerland, patricia.sidharta@idorsia.com.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20190322
PL  - New Zealand
TA  - Drug Des Devel Ther
JT  - Drug design, development and therapy
JID - 101475745
RN  - 0 (Endothelin Receptor Antagonists)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Endothelin)
RN  - 0 (Sulfonamides)
RN  - MZI81HV01P (aprocitentan)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Body Weight/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Drug Tolerance
MH  - Endothelin Receptor Antagonists/administration & dosage/*adverse 
      effects/blood/*pharmacokinetics
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Pilot Projects
MH  - Pyrimidines/administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Receptors, Endothelin/*metabolism
MH  - Sulfonamides/administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Young Adult
PMC - PMC6435120
OTO - NOTNLM
OT  - aprocitentan
OT  - endothelin
OT  - endothelin receptor antagonist
OT  - first-in-human study
OT  - pharmacodynamics
OT  - pharmacokinetics
COIS- Disclosure JD is a fellow of the American College of Clinical Pharmacology. PNS 
      and JD are current employees of Idorsia Pharmaceuticals Ltd and former employees 
      of Actelion Pharmaceuticals Ltd. MM is a current employee of Idorsia 
      Pharmaceuticals Ltd. MKK was the principal investigator of the study that was 
      sponsored by Actelion Pharmaceuticals Ltd. The authors report no other conflicts 
      of interest in this work.
EDAT- 2019/04/10 06:00
MHDA- 2019/09/17 06:00
PMCR- 2019/03/22
CRDT- 2019/04/10 06:00
PHST- 2019/04/10 06:00 [entrez]
PHST- 2019/04/10 06:00 [pubmed]
PHST- 2019/09/17 06:00 [medline]
PHST- 2019/03/22 00:00 [pmc-release]
AID - dddt-13-949 [pii]
AID - 10.2147/DDDT.S199051 [doi]
PST - epublish
SO  - Drug Des Devel Ther. 2019 Mar 22;13:949-964. doi: 10.2147/DDDT.S199051. 
      eCollection 2019.